To determine whether decreased antidepressant medication response in LLD patients with ED and WMH is caused by a loss of expectancy effects, we will evaluate 130 outpatients with LLD at baseline to determine their degree of ED (interference score on Stroop Color-Word Test), WMH burden (severity score on Fazekas modified Coffey Rating Scale derived from anatomical MRI), and white matter tract integrity (using diffusion tensor imaging [DTI]). Building on work from my K23 Award, we will manipulate participants' expectancy of improvement in an 8-week duration antidepressant trial by randomizing them between open administration of escitalopram (i.e., high expectancy) and placebo-controlled administration of escitalopram (i.e., low expectancy). The difference in antidepressant response observed between open and placebo-controlled medication treatment is a measure of the expectancy contribution to outcome, which is substantial in younger depressed adults but we hypothesize will be diminished in LLD patients with ED and WMH.